1. Field of the Invention
The invention concerns 2-O- and 5-O-substituted 1.4;3.6-dianhydrohexitol mononitrates of the general formula I, ##STR2## wherein R is a halogen-substituted phenyl group, a methanesulphonyl or nicotinoyl group, as well as their physiologically acceptable acid-addition salts, insofar as R signifies the nicotinoyl group.
The basic structure of these compounds consists of the stereoisomeric 1.4;3.6-dianhydrohexitols which can be converted into one another by epimerisation, namely, either 1.4;3.6-dianhydro-L-iditol (= "isoidide") (II), ##STR3## in which the OH groups in the 2- and 5-position each have the exo configuration, or 1.4;3.6-dianhydro-D-glucitol (= "isosorbide") (III), ##STR4## which has a 2-exo-standing and a 5-endo-standing OH group and thus--in the case of different substituents in the 2- and 5-position--occurs in two isomeric forms.
Finally, the basic structure of some compounds consists of 1.4;3.6-dianhydro-D-mannitol (= "isomannide") (IV), ##STR5## which has two endo-standing OH groups.
Since, in contradistinction to the glucitol derivatives, in the case of the iditol and mannitol derivatives a differentiation between the 2- and 5-substituents is not possible because the C.sup.2 -atom, in the case of rotation of the molecule through 180.degree., becomes the C.sup.5 -atom, references to the 5-position or 2-position of substituents are, in the case of these derivatives, superfluous. However, for a better comparison of the structures of the individual compounds with the general formulae, the isoidide derivatives are here referred to as 5-O-position-substituted isoidide derivatives since they can be prepared by nucleophilic substitution, with reversal of configuration, for example from 5-O-alkylsulphonyl- or 5-O-arylsulphonyl-isosorbide.
2. Description of the Prior Art
A brief survey of the stereoisomerism of the 1.4;3.6-dianhydrohexitols is given by J. A. Mills in Advances in Carbohydrate Chem., 10, 1-53 (1955).
The invention also concerns processes for the preparation of the initially mentioned 2-O - and 5-O-substituted 1.4;3.6-dianhydrohexitol mononitrates, as well as pharmaceutical compositions which contain the compounds according to the invention.
The nitrates of 1.4;3.6-dianhydro-D-glucitol (also called 1.4;3.6-dianhydro-D-sorbitol) are known e.g. from U.S. Pat. No. 3,886,186, namely, not only the 2- and 5-mononitrates but also the 2,5-dinitrate of isosorbide. These nitrates, especially the dinitrate, which is already commercially available as a medicament, are pharmacologically active substances with haemodynamic, vasodialatory and antianginous effectiveness which are especially employed in the case of coronary insufficiency and for the treatment of angina pectoris.
Furthermore, from U.S. Pat. No. 3,886,186 there are also known the 5-acetate-2-nitrate, 2-acetate-5-nitrate, 2-ethylate-5-nitrate, 5-nitrate-2-sulphamate, 2-carbamate-5-nitrate and the 5-carbamate-2-nitrate of isosorbide, as well as the corresponding propionate, butyrate, isobutyrate, caproate and benzoate mononitrates.
Furthermore, the p-toluenesulphonic acid esters of the mononitrates of isoidide, isosorbide and isomannide are known (Can. J. Chem., 45, 2191-2194 (1967)). However, only the infra-red spectra of these compounds have hitherto been described in detail. On the other hand, nothing has become known regarding the pharmacological properties of the compounds.
The pharmacokinetics of the dinitrate and mononitrates of isosorbide, isomannide and isoidide have been described by Bogaert and Rosseel in Naunyn-Schmiedeberg's Arch. Pharmacol., 275, 339 (1972).
However, it has been shown that the nitrates cause unpleasant side effects, especially headaches. Furthermore, the mononitrates are more poorly resorbed than, for example, isosorbide dinitrate (ISDN). In addition, the dinitrates of isosorbide, isomannide and isoidide can only be prepared and handled with special precautionary measures since they are explosive.